Iron metabolism/Anemias Flashcards
(31 cards)
What are the major ways to control iron balance? Is there a way to excrete iron? How much iron is there in one RBC?
- Dietary uptake
- Release of iron from macrophages and liver
NO MECHANISM FOR IRON EXCRETION
RBC contains 1 mg of iron/mL
What foods inhibits iron adsorption and what foods increase iron adsorption?
Inhibit
Oxalates - ex. spinach, tea
Phylates - ex. soy, almond
Calcium - ex. milk
Antacids
Polyphenols
Tannins - ex. coffee, tea
Increase
Alcohol
Red meat
Vit C and A
Fresh fruit and juice
Where does iron absorption occur? What are the 3 steps in iron absorption. Describe and explain.
Occurs in enterocyte (intestinal epithelial cells)
- Transfer of iron within cytosol of enterocyte
- Once within cytoplasm, iron is shuttled by a small MW transport peptides which retains the iron redox state
- Iron can be stored as ferritin or transported through the basolateral membrane and into circulation through ferroportin - Transfer of iron from cytosol to plasma
- Major pathway:
a. transport of Fe2+ across basolateral surface via FERROPORTIN
b. Fe2+ oxidized to Fe3+ by HEPHAESTIN
c. Fe3+ binds to TRANSFERRIN (Tf) and is transported to various tissue/cells
- Minor pathway:
a. Fe2+ directly transported into plasma via a transmembrane iron transporter
b. CERULOPLASMIN oxidizes it into Fe3+ and is bound by Tf - Iron uptake into plasma into tissues
- Transferrin receptor 1 (TFR1) is expressed on cell surface and is responsible for taking up Tf-bound iron
- Involve receptor mediated endocytosis
- Vesicles acidified and iron is released from Tf
- ApoTf recycled back to cell surface
What are the different pathways in the regulation of iron absorption? Describe and explain.
- Hepcidin pathway
Hepcidin -> produced by liver and regulates iron absorption by binding to ferroportin
- Naturally tries to inhibit iron absorption to prevent bacteria from utilizing iron as bacteria needs iron for growth
- Plays a role in anemia of chronic inflammation - Intracellular regulation of iron metabolism
The synthesis of transferiin receptor (TfR), ferritin and DMT1 is regulated post-transcriptionally
- mRNA for each of these proteins contain 1 or several IRON RESPONSE ELEMENTS (IREs)
In iron depeleted cells:
- Iron regulatory protein (IRP) binds to 5’ IRE which prevents the initiation of translation and inhibits ferritin synthesis
- IRP binds to 3’ IRE of TfR which stablizes mRNA and increases translation
When iron is high in cells:
- Efficient translation of ferritin mRNA and ferritin synthesis proceeds
- TfR mRNA is destabilized which reduces translation of TfR
What are the two forms of iron storage? Where are they found?
Ferritin
- 48000 MW
- Highest conc in LIVER, SPLEEN, BM
Hemosiderin
- Denatured form of ferritin
- If cells overloaded with iron, hemosiderin accumulates in the lysosomes (mainly found in MACROPHAGES)
Difference between absorption of heme vs non-heme iron.
Heme absorption - well absorbed (ex. meat)
Iron uptake not regulated
~ 10% of total iron intake
Non-heme absorption - less well absorbed (ex. nuts)
Iron uptake tightly regulated
~ 90% of iron in diet
What is the process of heme absorption?
- Heme iron is taken up by endocytosis
- Fe(2+) is liberated from heme within endosome/lysosome by Heme Oxygenase (HO) that cleaves porphyric ring
- Proceed similar to non-heme absorption
What is the process of non-heme absorption?
- Enterocytes are incapable of binding and absorbing Fe(3+), ferro-reductase reduced Fe(3+) to Fe(2+)
- Fe(2+) bound and transported into the enterocyte by divalent metal transporter (DMT-1) channels
What are the different proteins involved in iron metabolism and regulation? State their names and functions.
Transferrin - Transports iron in plasma
DMT1 - transport ferrous iron from gut lumen into enterocyte
Duodenal cytochrome b (DCYTB) - reduces Fe3+ to Fe2+ that can be transported by DMT1
TfR1 - delivers iron from plasma into erythroid precursors in the bone marrow and other cells in the body
Ferritin - major iron storage protein
Hepcidin - regulates iron absorption and release of iron from macrophages
*What happens when there is an increase or decrease in hepcidin production in the liver?
Increase hepcidin -> hepcidin binds and inhibits ferroportin which blocks iron export into the blood circulation
Decreased hepcidin -> ferroportin is free to export iron from enterocytes and macrophages which increases iron absorption and recycling
Is excess iron good or bad? Why?
Bad - If the capacity of ferritin to store iron is exceeded, iron is stored in liver cells and other tissues which can take up non-Tf-bound iron from the plasma, causing significant damage
- Unbound (free) iron is toxic, because it catalyzes the generation of potent free-radical species via the Fenton and Haber-Weiss reactions
- Iron can produce abundant quantities of hydroxyl radical (OH) from less reactive oxygen species
- Hydroxyl radical (OH) cause irreversible oxidative damage to DNA, lipids and proteins a.k.a oxidative stress
How can body iron content accumulate?
- Increased intestinal iron absorption
- Ineffective erythropoiesis
- Iron is injected into the body
- Liver disease
What is Hereditary Hemochromatosis? What is it, why does it happen and what are the clinical manifestations? What can we do to treat this disease?
Hereditary Hemochromatosis is a disorder of excess iron that is caused by increased intestinal iron absorption.
- autosomal recessive disorder
- disrupts the body’s regulation of iron that results in toxic accumulation of iron in vital organs
Cause - Genetic mutation in genes responsible for regulating Hepcidin
- Mutations: HFE Cys282Tyr and His63Ap
CM - occur in 5th decade or later
- High transferrin saturation (>45% men, 55% women)
- High ferritin
Treatment
- Phlebotomy
- Donate blood if meet all other criteria
What is anemia? What causes anemia?
Anemia is a condition in which there is reduced proportion of RBCs
Causes
1. Too little iron
2. Too little Hb
3. Too little RBCs
-> decreased production
-> increased destruction
-> loss of RBC like bleeding
What are useful blood indices used for the classification of anemia?
MCV = Mean Cell Volume
Measurement of size and volume of RBC
High MCV = large RBC cell size
Low MCV = Small RBC cell size
Reticulocytes = Immature RBCs
Helps to determine whether anemia is due to production/destruction
Low reticulocyte = production prob
High reticulocyte = increased destruction/blood loss
Other cell counts - neutrophils, platelets
What are the classifications of anemia?
Normocytic - Normal MCV
Microcytic - Low MCV
Macrocytic - High MCV
What are the subcategories of normocytic anemia?
Increased Reticulocyte
- Within RBCs
- Outside RBCs
Decreased or normal reticulocyte
What are the various disorders of normocytic (hemolytic) anemia due to problems within RBCs? (Increased reticulocyte)
- Hereditary Spherocytosis
- Inherited defects caused by mutations in RBC membrane cytoskeleton
- Spherocytes are formed - Hereditary Elliptocytosis
- Can be detected by blood smear examination showing >25% elliptocytes
- Heterogenous group of disorders caused by various mutations in genes affecting RBC cytoskeleton and membrane protein integrity
- Asymptomatic, some demonstrate hemolytic anemia and splenomegaly - RBC Enzyme Defect
- G6PD DEFICIENCY (“Fava Beans” hemolysis)
-> failure to generate adequate NADPH
-> erythrocytes susceptible to oxidation of Hb by oxidant radicals like h2o2
- PK DEFICIENCY
-> caused by a defect in glycolytic RBC metabolism
-> lack of ATP
-> incr RBC destruction - Sickle cell anemia
What are the various disorders of normocytic (hemolytic) anemia due to problems outside RBCs? (Increased reticulocyte)
Immune hemolytic anemia
1. Autoimmune hemolytic anemia (AIHA)
2. Alloimmune
Non-immune hemolytic anemia
1. Thrombotic thrombocytopenic purpura (TTP)
2. Hemolytic uremic syndrome
Causes FRAGMENTATION HEMOLYSIS
What is autoimmune hemolytic anemia (AIHA)? What are the 2 subgroups of AIHA?
Caused by auto-Ab-mediated destruction
Classified into 2 primary subgroups based on optimal temperatures at which Ab bind:
1. Warm AIHA - involves IgG Ab that react with RBC membrane at normal body temp
2. Cold AIHA - involves IgM Ab that bind to polysaccharides on RBC surface at low temp and then cause lysis on rewarming
- Can see “clumps” of RBC under microscope
What is alloimmune hemolytic anemia? What test used to diagnose? Describe the test.
Ab against a non-self Ag
Direct antiglobulin test (DAT)
1. Determines whether there is any Ab and/or complement binding to a patient’s RBC
2. Anti-human globulin reagent is added directly to patient’s washed RBCs
3. The occurrence of agglutination means that patient’s RBCs have Abs (self/non-self) binding to its surface
What is thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) caused by?
TTP - Life threatening disease characterized by deficiency in ADAMTS13 enzyme
HUS - Caused by shiga toxin-producing E.coli and shigella, usually from ingestion of uncooked ground meat
What is a disorder that causes decreased reticulocytes (or normal) in normocytic anemia?
Aplastic anemia - a.k.a bone marrow failure
- Reduced cellularity and less production of RBC, WBC and platelets in BM
What are the causes of microcytic anemia?
TAILS
T - Thalassemia*
A - Anemia of chronic inflammation*
I - Iron deficiency*
L - Lead poisoning
S - Sideroblastic anemia
